The primary goal of our NCDDG grant is to develop drugs that tightly bind to and specifically inhibit Src, a protein tyrosine kinase (PTK) implicated in a large number of human cancers (colon, breast, leukemia, neuroblastoma, lung adenocarcinoma, and gliomas). To achieve our programmatic goals, we created a multidisciplinary Program composed of 5 Programs and one administrative Core. All Programs are mutually interdependent in function. The First Program will focus on the design and synthesis of unique peptidomimetic inhibitors based on the conformationally constrained lead peptide (proprietary). The Second Program will provide combinatorial libraries of inhibitors based on a lead compound (proprietary) and structural information provided by NMR and other physical studies of Src and peptide inhibitors. The Third Program will test the inhibitors against Src and a panel of other kinases (Yes, Bcr-Abl, Her2/neu, Csk, FGF-R, PKA, Lck, hexokinase, and lactate dehydrogenase) to document specificity. The Fourth Program will determine basic drug stability, potential for gastrointestinal absorption, and basic animal bioavailability and biodistribution for selected drug candidates. The Fifth Program will evaluate the best inhibitors identified. The Third Program against tumor cell lines and normal cells in an effort to show selective action against tumor but not normal cells in culture. In addition, the Fifth Program will further e valuate appropriate drugs for antitumor activity against murine tumor models.